Lipid signaling Flashcards
(47 cards)
What components does lipid signaling involve?
Involves a lipid or lipid-derived molecule that binds to:
- receptor (first messenger)
- kinase/phosphatase (second messenger)
- protein (second messenger)
Why are lipid signaling molecules transported with carrier protein if they can diffuse through the membrane?
It is much faster and more efficient. And, once inside the cell, the lipid signaling molecule (unless a polar derivative) will still be insoluble.
Why are lipid signaling molecules made on demand?
They are often not stored, so they are made only when needed and kept in the circulation on carrier proteins.
Where are phosphoinositides present in the cell?
inner leaflet of plasma membrane
what type of messenger are PIs?
second messenger
Describe structure of phosphoinositides
phospholipid - one saturated FA and one unsaturated. Inositol head group. often phosphorylated at C3 and C4 (PI(3,4)P2)
Describe metabolism of phosphoinositide by PLC.
Inositol head group can be phosphorylated on 4 or 5 in any order, but needs to have both phosphorylated in order for PLC to act on it to produce IP3 and DAG
Numbering of inositol head group.
How is PLC activated?
It is activated in a number of ways:
- by RTK to make PLCy
- by GPCR and alpha q G protein subunit to make PLC beta1
- by GPCR and G subunit beta gamma to make PLC beta2
The isoforms all do the same thing!!
Is IP3 a lipid?
No it is lipid derived, but is itself a soluble molecule
What is the dowstream effect of DAG?
it activates PKC
What is the downstream effect of IP3?
it releases Ca2+ from the ER
What is PLC alpha isoform?
It is not actually an isoform, but a proeolytic fragment from PLC delta
What PLC isoform is expressed by lower eukaryotes and prokaryotes?
PLC delta
What part of the PLC protein is made up by the X and Y domains?
the catalytic core
What is the pleckstrin homology domain in PLC?
PDH is a domain that facilitates binding to the plasma membrane via PIP3. The alpha helices bind onto the phospholipid.
Discuss the regenerative cycle of phosphoinositide resynthesis.
After PI4,5bisphosphate is cleaved by PLC to IP3 and DAG, the two second messengers are recycled in different ways:
IP3:
- alkaline and acid phosphatases act on IP3 to create inositol
- inositol acts with CDP-DAG to form phosphoinositide
DAG:
- DAG removed from PI or made from cholesterol is coverted to phosphatidic acid
- phosphatidic acid is converted to CDP-DAG, which acts with inositol to form PI
Why is phosphoinositide recycling kept to a minimum?
It is metabolically expensive
What is DGK? What is it involved in?
DGK = diacylglyerolkinase is the kinase which activates DAG with phosphate, making it phosphatidic acid
- phosphorylation disrupts docking interactions of Ras, Rac, and PKC to DAG, downregulating the signals they transduce.
- this downregulation is called T cell anergy which is the opposite of division in the immune response
- is reversible. Phosphate just needs to be removed from phosphatidic acid
What is PI3K? What is its effect on phosphoinositide?
It can act on any substrate to add phosphate to the third carbon of PI. PIP3 is still in the membrane and acts as a docking station for proteins with the pleckstrin homology domain.
How is the PIP3 docking site disrupted?
PTEN dephosphorylated PIP3. PTEN is mutated in many tumors,
What are the early steps of PIP3 inhibition of apoptosis?
- activatesd RTK
- RTK phosphorylats and activates PI3K
- PI3K phosphorylates PIP2 to make PIP3.
- PDK1 and Akt can dock to PIP3 because they have PHD
- Akt is activated and goes on to inhibit apoptosis
Describe the role of PIP3 in scaffolding proteins.
PIP3 can help proteins with PHD hold onto docking stations to keep scaffolding between itself and RTK intact.
Describe the PI3K structure.
- p85 regulatory subunit
- p110 catalytic subunit
- 3 different classes with different subunit variations
